An amide mimic of desTHPdactylolide: Total synthesis and antiproliferative evaluation. (15th May 2021)

• Record Type: Journal Article
• Authors: Chen, Guanglin; Gonzalez, Maricarmen; Jiang, Ziran; Zhang, Qiang; Wang, Guangdi; Chen, Qiao-Hong
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 40(2021)
• Publication Date: 2021-05-15
• Subjects: Natural product -- Zampanolide -- Dactylolide -- Prostate cancer -- Cell proliferation -- Synthesis; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2021.127970
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: An amide mimic of desTHPdactylolide was synthesized via a 26-step transformation. Antiproliferative activity was evaluated against five prostate cancer cell lines. The lactam moiety can serve as a bioisostere for the lactone in desTHPdactylodide. Abstract: (−)-Zampanolide is a unique microtubule stabilizing agent (MSA) with covalent-binding mechanism and low nanomolar anitproliferative potency towards multi-drug resistant cancer cells. MSAs have a special connection with prostate cancer by inhibiting androgen receptor nuclear translocation. Zampanolide and the structurally related dactylolide have thus been sought after by us as lead compounds for development of anti-prostate cancer agents. DesTHPdactylolide is a simplified mimic of dactylolide and has previously been synthesized by us in both configurations, with the (17 R ) configuration being more potent in suppressing prostate cancer cell proliferation. The current study aims to synthesize an amide mimic of (17 R ) desTHPdactylolide that was anticipated to be metabolically more stable than (17 R ) desTHPdactylolide. To this end, the amide mimic has been successfully synthesized through a 26-step transformation from 2-butyn-1-ol. Our WST-1 cell proliferation assay in five human prostate cancer cell models indicated that the lactam moiety can serve as a bioisostere for the lactone in desTHPdactylolide.